The goal of this research is to further study the priming of macrophages produced by inescapable tail shock (IS). To this end, the first part of the grant will identify the physiological signal which primes macrophages during IS. Macrophage priming occurs in response to a stressor, therefore norepinephrine and corticosterone, chemical mediators elevated during stress, will be examined. The endogenous source of these mediators will be removed and replaced to evaluate their respective roles in macrophage pruning. As result of macrophage priming T-cell proliferation in response to antigen is suppressed. Studies in vitro indicate that the signal suppressing T-cell proliferation is released from the primed macrophage. Therefore, the aim of the second part of the grant will be to determine the suppressive signal. Activated macrophages release several mediators which can suppress T-cell proliferation. These include nitric oxide (NO), reactive oxygen species (ROS) and prostaglandin E2 (PGE2). The experiments proposed in the second part of the grant involve administering the antigen keyhole limpet hemocyanin (KLH), and then manipulating the availability of NO, ROS or PGE2 and evaluating T-cell proliferation. This research will provide a greater understanding of the relationship between stress and the immune response.